New drugs selective for histamine H3-receptors can be used to establish that these receptors are involved in the feedback control of histamine synthesis and release, and to demonstrate their distribution in the brain and peripheral tissues. These drugs provide new tools for affecting physiological and possibly pathological conditions in which histamine is involved.
The -galactosidase reporter gene, either free or complexed with various cationic vectors, was microinjected into mammalian cells. Cationic lipids but not polyethylenimine or polylysine prevent transgene expression when complexes are injected in the nucleus. Polyethylenimine and to a lesser extent polylysine, but not cationic lipids, enhance transgene expression when complexes are injected into the cytoplasm. This latter effect was independent of the polymer vector/cDNA ionic charge ratio, suggesting that nucleic acid compaction rather than surface charge was critical for efficient nuclear trafficking. Cell division was not required for nuclear entry. Finally, comparative transfection and microinjection experiments with various cell lines confirm that barriers to gene transfer vary with cell type. We conclude that polymers but not cationic lipids promote gene delivery from the cytoplasm to the nucleus and that transgene expression in the nucleus is prevented by complexation with cationic lipids but not with cationic polymers.
Altogether, these experiments suggest that cDNA digestion by cytosolic nucleases occur when the decomplexed transgene is present in the cytosol. We propose that the inefficient transfer of cDNA into the nucleus during transfection with synthetic vectors may result from rapid digestion of naked cDNA by a Ca2+-sensitive cytosolic nuclease.
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